Potentiation of diffuse lung damage by oxygen: determining variables.

The antioxidant, butylated hydroxytoluene (BHT), caused diffuse necrosis of type I alveolar cells in mouse lung followed by proliferation of type II epithelial cells. Exposure to oxygen during the phase of epithelial cell division led to the development of diffuse interstitial fibrosis. The extent of the fibrotic changes, as quantitated by measuring total lung hydroxyproline, was dependent upon both oxygen concentration in the inspired air and length of exposure. Fibrotic changes were seen in animals exposed after 400 mg/kg of BHT for 6 days to 50% oxygen or more, 3 days to 60% oxygen or more, or 2 days to 70% oxygen or more, but not if exposure was limited to 24 h only. Minimal fibrosis developed in animals exposed for 6 days to 80% oxygen alone. Additional factors determining the severity of fibrotic changes were the extent of the initial lung lesion caused by BHT and the time interval between BHT administration and the beginning of oxygen exposure. Potentiation of lung fibrosis was also observed in animals treated with methylcyclopentadienyl manganese tricarbonyl and 70% oxygen. We conclude that oxygen can severely aggravate lung damage caused by bloodborne agents, and that the severity of the resulting lesion is determined by many variables.